The joints of the skeletal system are the sites at which bones meet (articulate). In addition to bone, joints are formed by muscle, tendons and ligaments. Furthermore, protection of the joint is provided by cartilage and connective tissue, as well as by synovial fluid within the joint. When stressed, or as a result of the aging process, joints are prone to injury or degradation, leading to pain, impaired movement and decreased quality of life. Thus, approaches for repairing or treating damaged joints are highly desirable.
The earliest surgical approaches for joint repair involved cutting open the joint, referred to as open joint surgery or arthrotomy. However, because of the highly invasive nature of such procedures, the patient requires a hospital stay, often suffers severe and prolonged pain and faces a very long recovery time. In cases of extensive joint damage, surgical techniques have progressed such that reconstruction or replacement of the joint (arthroplasty) is an option. Again, however, these techniques are associated with considerable pain and recovery time for the patient.
The development of arthroscopic methods for articular surgery has greatly reduced the pain and recovery time experienced by patients as compared to arthrotomy. In arthroscopy, a small fiberoptic viewing instrument (the arthroscope), made up of a lens, light source and video camera, is inserted into the joint via a tiny (about ¼ of an inch) incision called a portal. Other portals are used for insertion of small (only 3 or 4 mm in diameter) surgical instruments. A video image is sent from the arthroscope to a television monitor, allowing the surgeon to have a clear view of the entire joint while operating. To maintain a clear field of view, the joint is continuously irrigated with an irrigation fluid during arthroscopic surgery. Various irrigation fluids have been tested, including water, 0.9% normal saline, Ringer's solution, 20% sorbitol, 2–10% mannitol and 1.5% glycine (Gradinger, R. et al. (1995) Arthroscopy 11:263–269; Mah E. T. et al. (1997) Arthroscopy 7:24–32). An irrigation fluid referred to as Synovisol, which is isomolar, nonhemolytic, nonantigenic, has a low viscosity and is nonconductive, has also been tested (Marshall, G. J. et al. (1988) Arthroscopy 4:187–193). A consequence of the need to continuously irrigate the joint during arthroscopy is that the normal synovial fluid is flushed from the joint.
The viscoelastic properties of synovial fluid are provided by the glycosaminoglycan molecule hyaluronan. Cross-linked forms of hyaluronan, referred to as hylans, have been used intra-articularly (for a review see e.g., Balazs, E. A. and Denlinger, J. L. (1989) Ciba Found. Symp. 143:265–275). For example, hylan fluid has been used as an irrigation fluid in arthroscopic surgery of the temporomandibular joint (McCain, J. P. et al. (1989) J. Oral Maxillofac. Surg. 47:1161–1168). Hyaluronic acid (HA-Hyalgan) and hylan G-F 20 (Synvisc) also have been used in the treatment of osteoarthritis (Frizziero, L et al. (1998) Clin. Exp. Rheumatol. 16:441–449; Marshall, K. W. et al. (2000) J. Orthop. Res. 18:416–425; Kroesen, S. et al. (2000) Clin. Rheumatol. 19:147–149). Use of hylan G-F 20 intra-articularly, however, has been reported in at least one case to induce an acute attack of calcium pyrophosphate dihydrate arthritis (Kroesen, S. et al. (2000) Clin. Rheumatol. 19:147–149). Na-hylan, a chemically modified sodium hyaluronate jelly, also has been used to reduce postsurgical tendon adhesions (Weiss, C. et al. (1986) Bull. Hosp. Jt. Dis. Orthop. Inst. 46:9–15; Weiss, C. (1987) Bull. Hosp. Jt. Dis. Orthop. Inst. 47:3139).
Arthroscopy has now become a common surgical procedure in current medical practice with almost 700,000 knee and shoulder arthroscopies performed each year in the United States. The post-operative course for these patients is marked by significant pain and resultant loss of limb function for the initial 3–5 days. Therapeutic intervention typically involves injection of a local anesthetic (e.g. bupivacaine) into the operated joint at the end of the procedure, resulting in pain relief for about 6 hours. It has been suggested that an intra-articular dose of approximately 10 mg produces analgesia of the joint (Creamer J. Rheumatol. (1996) 23:1031–1036). Thereafter, the patient is managed by administration of oral narcotics (e.g. Vicodin) and/or acetaminophen, and often neither of these results in sufficient pain relief. There exists a clinical need for a single dose product that can provide short term (2–5 days) post-arthroscopy pain relief.
Other surgical procedures are also often associated with significant pain, such as incisional pain. Such procedures include, most often, abdominal, breast and spinal operations, including cesarean births, hernia repair, hysterectomy, mastectomy, and breast augmentation. Other surgery involving pain or discomfort due to incision includes podiatry procedures.
An exogenous fibrin clot is another type of material that has been used in joint repair. An exogenous fibrin clot has been shown to promote fibrocartilaginous repair in an animal model of triangular fibrocartilage complex (TFCC) injury (Whately, J. S. et al. (2000) Arthroscopy 16:127–136). Furthermore, an exogenous fibrin clot has been used to enhance repair of an injured meniscus (Rodeo, S. A. and Warren, R. F. (1996) Clin. Sports Med. 15:469–481).
U.S. Pat. No. 3,949,073 by Daniels et al., U.S. Pat. No. 4,140,537 Luck et al., U.S. Pat. No. 4,424,208 by Wallace et al., U.S. Pat. No. 5,002,071 by Harrell, U.S. Pat. No. 4,760,131 by Sundsmo et al., EP 338813 by Tsunenaga et al. and U.S. Pat. No. 4,582,640 by Smestad et al. describe collagen formulations for use in soft tissue or connective tissue augmentation, for example reduction of skin wrinkles or scars. U.S. Pat. No. 4,764,377 by Goodson and U.S. Pat. No. 4,906,670 by Higashi et al. describe compositions containing collagen for the treatment of periodontal disease.
U.S. Pat. Nos. 6,083,918 and 6,165,983 by Klaus describes the use of collagen formulations for the treatment of degenerative arthrothopies while U.S. Pat. No. 3,966,908 by Balassa describes the use of cartilage powder for such treatments. Neither Klaus nor Balassa teach the use of particular types of collagen. Collagen from bovine skin sources, as used in Klaus, is generally Type I collagen, but, without further processing, would contain immunogenic telopeptide sequences (Rubin et al. (1965) Biochemistry 4(2):181–190). The collagen in cartilage powder is predominantly Type II collagen, which is frequently used to provoke immunogenic reactions in rats and other animals in order to model rheumatoid arthritis (Myers et al. (1997) Life Sci. 61(19):1861–1878; Brahn (1991) Clin. Orthop. 265:42–53). Steffen (1975) A. Immun.-Forsch. Bd. 150:432–446) examines the immunogenicity of soluble human collagen in rabbit knees. U.S. Pat. No. 4,704,273 by McMichael describes collagen containing formulations for the treatment of rheumatoid arthritis.
U.S. Pat. No. 5,639,796 by Lee et al. describes a composition comprising a hydrophilic polymer suspended in a hydrophobic carrier and its use for replacing natural lubricating fluids of the body.
U.S. Pat. No. 4,703,108 by Silver et al. describes the production of biodegradable matrices using crosslinked collagen.
Despite advances in articular surgical methods, there still exists a need for approaches that are effective in diminishing patient pain, increasing joint mobility post-surgery and/or reducing recovery time and that are generally applicable to the various articular surgery options (e.g., arthrotomy, arthroscopy, arthroplasty) or other surgical procedures associated with incisional pain. When providing extended treatment of pain or discomfort, as through the controlled release of pharmaceutical agents, it is essential that the compositions or devices employed for the controlled release of substances are non-immunogenic and well tolerated by the patient (Cooperman et al. (1984) J. Am. Acad. Dermatol. 10:638–646; DeLustro et al. (1988) Dermatol. Surg. Oncol. 14:57–65; DeLustro et al. (1987) Plast. Reconstruct. Surg. 79:581–592; Frank et al. (1991) Plast. Reconstruct. Surg 87:1080–1088).
Citation of the references above is not an admission that these references, or the information disclosed therein, is prior art.